CLINICAL CORE: Project Summary/Abstract Frontotemporal lobar degeneration (FTLD) is a young-onset neurodegenerative condition. The major pathologies causing FTLD include misfolded forms of tau known as FTLD-Tau, TDP-43 proteinopathy known as FTLD-TDP, and other very rare FTLD variants. It is crucial to find features identifying these pathologic forms of FTLD during life to develop reliable diagnostic markers and establish eligibility for disease-modifying therapy trials. Mutations associated with these pathologies are found in 15% of cases. The vast majority of FTLD patients have sporadic disease, but clinical features do not reliably predict FTLD-Tau or FTLD-TDP histopathology, and up to 25% of patients who present with clinical frontotemporal degeneration (FTD) are atypical forms of autopsy-confirmed Alzheimer?s disease (AD). It is thus necessary to collect additional data that reflect the pathologic form of FTLD during life more accurately. This includes clinical, neuropsychological, neuroimaging, genetic markers including single nucleotide polymorphisms (SNPs), and cerebrospinal fluid (CSF) biomarkers. Moreover, disease-modifying treatment trials require well-characterized natural histories of FTLD-related phenotypes to identify markers of a beneficial treatment response. The Clinical Core will work with other cores and projects of this Program Project Grant (PPG) to improve our understanding of disease mechanisms. To this end, we will continue to recruit patients with sporadic clinical FTD who have a high likelihood of having FTLD spectrum pathology, and asymptomatic and symptomatic carriers of mutations associated with FTLD. We will collect multimodal data to help identify the specific form of FTLD pathology to improve diagnostic accuracy in sporadic cases and characterize longitudinal progression, and we will recruit these patients for autopsy. We propose four Specific Aims to achieve these goals.